The innate immune system recognizes microbial pathogens via pattern recognition receptors that signal host defense mechanisms. Here we propose to study the immunological role of two pattern recognition receptors involved in the detection of HIV-1, Toll-like receptor 8 (TLR8), which recognizes HIV-1 ssRNA, and the C- type lectin CD209 (aka DC-SIGN). We reported that TLR activation leads to the induction of CD209, thus linking these two families of pattern recognition receptors. Specifically, activation of TLRs triggers the rapid differentiation of monocytes into two distinct populations of cells: CD209+ macrophages and CD1b+ dendritic cells. Here, we propose to investigate the role of TLRs and CD209 in HIV pathogenesis. First, we will determine whether HIV-1 ssRNA, a TLRS ligand, can also induce the differentiation of monocytes into CD209+ macrophages and CD1b+ dendritic cells, the mechanism for induction of these subsets and the relative expression of HIV-1 co-receptors on these innate immune populations. Second, the ability of CD209+ macrophages and CD1b+ dendritic cells to contribute to host defense and disease pathogenesis will be compared by determining the ability of CD209+ macrophages and CD1b+ dendritic cells to bind/internalize HIV-1, to support or inhibit viral replication and to facilitate HIV-1 infection of T cells in trans. By examining the functional role of CD209+ macrophages and CD1b+ dendritic cells, our studies will determine the mechanisms by which TLR8-induced differentiation of monocytes into macrophages and dendritic cells leads to host defense and/or disease pathogenesis. The identification of CD209 as being expressed predominantly on macrophages provides a new avenue for research, since this receptor is known to facilitate HIV-1 entry into cells. Together, the experiments outlined in this proposal will provide valuable insight into the role of the innate immune system in HIV-1 pathogenesis well as providing new strategies for therapeutic intervention in HIV-1 disease. [unreadable] [unreadable] [unreadable]